From GWAS to functional studies: Tackling the complex nature of brain disorders

Descripción del proyecto

Traducción de los hallazgos de los estudios de asociación de genoma completo en mecanismos de enfermedades

Los estudios hologenómicos de asociación (GWAS, por sus siglas en inglés) tienen como objetivo encontrar vínculos entre los fenotipos y los genotipos mediante el cribado de miles de variantes genéticas de múltiples «loci». Los GWAS han identificado «loci» genéticos que contribuyen al riesgo de rasgos o enfermedades de interés como las encefalopatías. Sin embargo, esta información no ha mejorado la comprensión de los mecanismos de las enfermedades, principalmente debido a la heterogeneidad observada. Los científicos del proyecto GWAS2FUNC, financiado con fondos europeos, se proponen abordar este problema mediante el desarrollo de herramientas para acortar la brecha entre los GWAS y una función. Una traducción más eficaz de los hallazgos de los GWAS en información sobre el mecanismo hará avanzar nuestros conocimientos sobre la patogenia de las encefalopatías.

Objetivo

Genome-wide association studies (GWAS) of unprecedented sample size have recently provided robust insight into the polygenic architecture of many different brain disorders. Despite this exciting potential, GWAS results have rarely translated into mechanistic disease insight. This is because the detected genetic effects are small and numerous, and hardly ever directly actionable for functional follow-up. In addition, the polygenic nature of brain disorders comes with large genetic heterogeneity, where different patients with the same disorder may carry completely different combinations of genetic risk variants, possibly corresponding to different etiological mechanisms, requiring different treatment regimens. To benefit from GWAS, extensive biological interpretation and insight into genetic heterogeneity is needed. In this ERC I will develop much needed tools for (i) extensive biological interpretation at cellular resolution and (ii) assessing genetic heterogeneity, both aimed at formulating hypotheses that take into account the polygenic nature of brain disorders and can be tested in functional experiments. I will apply the developed tools to a wide range of brain-related traits, providing ample starting points for functional follow-up. As a proof-of-concept I will test the viability of two neuroscientific approaches (iPSC and DREADDs) for functional follow-up of GWAS results. First, I will conduct scRNA sequencing and electrophysiological assessments on iPSC derived neurons and astrocytes from genetically selected (schizophrenia) patients and controls. Second, I will use in vivo chemogenetic manipulation to target specific cell types that have been implicated by GWAS (for insomnia). The primary goal of this proposal is to bridge the gap between GWAS and function. The results will facilitate the translation of GWAS findings for brain disorders into functional mechanisms that are biologically important in disease pathogenesis and, ultimately, treatment design.